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Clin Pharmacol Ther ; 88(2): 204-13, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20164833

ABSTRACT

Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad-TetOn-Flt3L + HC-Ad-TK in rats. Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survival in approximately 70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials.


Subject(s)
Adenoviridae/genetics , Brain Neoplasms/therapy , Genetic Vectors/pharmacokinetics , Genetic Vectors/therapeutic use , Glioblastoma/therapy , Adenoviridae/immunology , Adjuvants, Immunologic/therapeutic use , Animals , Behavior, Animal , Brain Neoplasms/psychology , Clinical Trials, Phase I as Topic , Dose-Response Relationship, Immunologic , Gene Dosage , Genetic Therapy , Genetic Vectors/adverse effects , Glioblastoma/psychology , Humans , Immunohistochemistry , Injections , Neoplasm Transplantation , Rats , Survival Analysis , Tissue Distribution , Transgenes/genetics
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